1. Field of the Invention
This invention relates to carbamate compounds having utility as anti-cancer agents and methods for their preparation and use.
2. Description of Related Art
The passage of proteins into and out of the nucleus of eukaryotic cells is a tightly controlled active transport process, referred to as nuclear import (or export). A protein to be transported contains a characteristic short amino acid sequence, called a nuclear localization sequence (“NLS”) or a nuclear export sequence (“NES”) identifying it as “cargo protein” to be imported or exported, respectively. A transport factor protein recognizes the NLS or NES and binds to the cargo protein and ferries it across the nuclear pore complex, which is the portal through which entry into and exit from the nucleus occurs. A transport factor that mediates nuclear import is called an importin; conversely, one that mediates nuclear export is called an exportin.
An exportin is CRM1, also referred to as exportin 1. Another protein involved in nuclear export is Ran, which is found in a guanine triphosphate bound form (“Ran-GTP”) and a guanine diphosphate bound form (“Ran-GDP”). Inside the nucleus, CRM1 forms a ternary complex with Ran-GTP and a cargo protein. The complex exits the nucleus through the nuclear pore complex and into the cytoplasm. There, the protein RanGAP activates the intrinsic ATPase activity of Ran-GTP, converting it to Ran-GDP and causing the ternary complex to dissociate and release the cargo protein. Then CRM1 re-enters the nucleus, to start the cycle anew. If nuclear export is inhibited, normal cell cycle progression is disrupted and apoptosis may occur.
Leptomycin B (“LMB”, formerly known as elactocin, NSC 364372, or PD 114720) is an anti-tumor, anti-microbial natural product originally isolated from Streptomyces spp., as reported in Hokanson et al., U.S. Pat. No. 4,771,070 (1988) and Nettleton et al., U.S. Pat. No. 4,792,522 (1988).

Subsequently, it was discovered that LMB is a covalent inhibitor of CRM1. Among the CRM1 cargo proteins whose nuclear export is consequently inhibited by LMB are p53, p73, STAT1, (i)ADAR1, Rev, actin, and Bcr-ab1. See, e.g., Nishi et al., J. Biol. Chem. 1994, 269 (9), 6320-6324; Fukuda et al., Nature 1997, 390, 308-311; Kudo et al., Exp. Cell Res. 1998, 242, 540-547. Many of these cargo proteins are implicated in cancer, leading to interest in LMB as a potential anti-cancer agent. Komiyama et al., J. Antibiotics 1985, 38 (3), 427-429; Wang et al., US 2003/0162740 A1 (2003). However, the cytotoxicity of LMB towards mammalian cells (Hamamoto et al., J. Antibiotics 1983, 36 (6), 639-645) offsets its potential as an anti-cancer agent. A phase 1 trial of LMB was halted in 1994 due to extreme toxicity. Newlands et al., Br. Cancer J. 1996, 74, 648-649.
LMB is the archetype of a natural product family referred to as the leptomycin family, characterized by a 2,3-dehydro-δ-valerolactone ring at one end of the molecule (C1-C5) and an extended carbon chain having a 6E,8Z and a 12E,14E diene system located off C5. For a review on the chemistry and biology of the leptomycin family, see Kalesse et al., Synthesis 2002, 8, 981-1003. Other members of the leptomycin family include leptomycin A, ratjadone, anguinomycins A-D, callystatin A, kazusamycin A (formerly known as CL-1957B), kazusamycin B (formerly known as CL-1957E), leptolstatin, and leptofuranins A-D. The structures of some of the other members of the leptomycin family are shown below:

Studies on the structure activity relationship of the leptomycin family compounds have been sparse. Kudo et al., supra, showed that the nitromethyl valerolactone derivative of LMB is inactive, suggesting that the 2,3-dehydro-δ-valerolactone moiety is an essential pharmacophore. Kuhnt et al., Applied Environ. Microbiol. 1998, 64 (2), 714-720, subjected LMB to bioconversion by a number of bacteria and fungi, resulting in several derivatives. Dong et al., US 2005/0272727 A1 (2005) and Dong et al., WO 2007/033214 (2007), disclose amides and esters, respectively, of leptomycin family compounds.

The disclosures of the documents cited in this section are incorporated herein by reference.